RESUMEN
Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 µg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.
RESUMEN
The parafascicular thalamic nucleus (nPf) is a critical relay in the ascending system that mediates motor control in the central nervous system (CNS). Yet, little is known about whether or not the nPf is involved in the development of morphine dependence and withdrawal. In the present study, kainic acid was used to chemically destroy the nPf in Wistar rats, and morphine dependence and withdrawal models were established. Morphine withdrawal symptoms score was evaluated in each group. An electrophysiological method was used to measure the changes in spontaneous discharge of nPf neurons. mu-Opioid receptor (MOR) mRNA level in nPf was detected using semi-quantitative RT-PCR. The ultrastructural alterations were examined by transmission electron microscopy. Results showed that the bilateral lesion of nPf had a marked influence on the development of morphine dependence and withdrawal. In order to address the mechanisms underlying, we found: (1) the average frequency and sum of nPf neurons that exhibited spontaneous discharge were increased in the morphine withdrawal group in comparison with the sham model group (P<0.05); (2) MOR mRNA level in the nPf of the morphine dependence group was decreased in comparison with that of the sham model group (1.45+/-0.38 vs. 5.37+/-0.94, P<0.01). In the morphine withdrawal group, which underwent 40 h withdrawal, the MOR mRNA level was higher than that in the morphine dependence group (2.97+/-0.73 vs. 1.45+/-0.38, P<0.05) but still lower than that in the sham model group (P<0.05); (3) the ultrastructural injuries of nPf neurons, which were in the nucleus, organelles and neuropil, were marked in the morphine dependent and withdrawal groups. Our study indicated that nPf played an important role in the development of morphine dependence and withdrawal. The results suggest that nPf may become a therapeutic target for treating morphine withdrawal syndrome.
Asunto(s)
Núcleos Talámicos Intralaminares/efectos de los fármacos , Núcleos Talámicos Intralaminares/patología , Dependencia de Morfina/patología , Morfina/farmacología , Síndrome de Abstinencia a Sustancias/patología , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patología , Desnervación , Modelos Animales de Enfermedad , Electrofisiología , Núcleos Talámicos Intralaminares/fisiopatología , Ácido Kaínico , Masculino , Microscopía Electrónica de Transmisión , Dependencia de Morfina/metabolismo , Dependencia de Morfina/fisiopatología , Narcóticos/farmacología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/patología , Neurotoxinas , Orgánulos/efectos de los fármacos , Orgánulos/metabolismo , Orgánulos/patología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores Opioides mu/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatologíaRESUMEN
To determine whether the receptor for advanced glycation endproducts (RAGE) contributes to cerebral ischemia, we evaluated RAGE expression in human cerebral ischemia and a model of permanent middle cerebral artery occlusion (pMCAO) in rats. Biopsy specimens were obtained from 12 patients with unilateral cerebral infarction. For the pMCAO model, the middle cerebral artery (MCA) of Sprague-Dawley (SD) rats was permanently occluded. Immunohistochemistry and Western blotting were used to measure RAGE expression in the ischemic hemisphere relative to the normal hemisphere. PC12 cells subjected to oxygen and glucose deprivation (OGD) were used to evaluate the role of RAGE in cell injury. As expected, cerebral ischemia patients expressed elevated levels of RAGE in the ischemic hemisphere. In 1 and 2 days pMCAO rats, levels of RAGE were higher in the ischemic hemisphere relative to the non-ischemic hemisphere, and expression was primarily located in the penumbra of the ischemic hemisphere. In PC12 cells, levels of RAGE increased after 7h of OGD culture. Notably, blockade of RAGE with a selective RAGE antibody in vitro reduced the cytotoxicity caused by OGD. The present data suggest that RAGE is up-regulated in human cerebral ischemia and pMCAO rats, suggesting a role for RAGE in brain ischemia.
